It is known that 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine of the formula (IA)
(hereinafter referred to as “olanzapine”) is a valuable antipsychotic drug.
Olanzapine was described for the first time in EP 454,436. According to the final step of the synthesis provided in said patent specification 4-amino-2-methyl-10H˜thieno[2,3-b]-[1,5]benzodiazepine hydrochloride of the formula (II)
is reacted with an excess amount of N-methylpiperazine for 20 hours under nitrogen atmosphere, in a 1:1 mixture of toluene and dimethyl sulfoxide, at the boiling point of the mixture, and the reaction mixture is cooled to 50° C. Olanzapine is crystallized by adding some water to the mixture and the thus-obtained crude product is recrystallized from acetonitrile. The desired olanzapine is obtained in a yield of 48%. The reaction is depicted in reaction scheme 1 as set forth in FIG. 1.
International patent application WO 2004/094433 A1 provides two new polymorphic forms of olanzapine dihydrochloride, and furthermore provides a new polymorphic olanzapine monohydrochloride.
European patent specification No. 733,635 discloses the preparation of olanzapine of so-called “technical quality”. This process is also carried out according to reaction scheme 1, with the difference that six times the amount of dimethyl sulfoxide is used at a temperature of 120° C. The reaction is detected by HPLC. The reaction is performed until 5% of residual starting substance of the formula (II) has remained in the mixture. Then it is cooled to 20° C. and olanzapine is crystallized at 5° C. by subsequently adding a tenfold amount of methanol and a threefold amount of water to the mixture. The yield of the thus-obtained crude olanzapine base amounts to 76.7%.
The inventors of the present invention have repeated the above reaction carried out in dimethyl sulfoxide or in a 1:1 mixture of toluene and dimethyl sulfoxide as specified in the prior art. During the reproduction it has been found that an undesirable amount of olanzapine N-oxide of the formula (III)
is formed even if the reaction is carried out under inert gas atmosphere (e.g. nitrogen or argon). This is even more surprising because—according to the experiments of the inventors of the present invention—dimethyl sulfoxide does not oxidize olanzapine, in spite of that according to many publications available in the literature dimethyl sulfoxide acts as an oxidizing agent. In spite of this fact, if dimethyl sulfoxide is applied as solvent for the reaction depicted in reaction scheme 1, a higher amount of the undesired the N-oxide of the formula (III) is formed. The stricter and stricter analytical requirements established for pharmaceutical substances call for the strongest possible decrease in the amount of impurities, such as the N-oxide of the formula (III). According to the experiences of the inventors of the present invention the amount of the impurity of the formula (III) being present in the pharmaceutical composition containing olanzapine as active ingredient increases during storage. Due to the structural similarity between olanzapine and its N-oxide of the formula (III) the separation of the two compounds—that is the removal of the impurity of the formula (III)—is cumbersome on the one part and inevitably leads to losses on the other.